US5196577A - Compound marked with tritium, its preparation and its use in particular in the determination of the affinity of retinoids for their nuclear receptors and their cytosolic binding protein - Google Patents

Compound marked with tritium, its preparation and its use in particular in the determination of the affinity of retinoids for their nuclear receptors and their cytosolic binding protein Download PDF

Info

Publication number
US5196577A
US5196577A US07/400,537 US40053789A US5196577A US 5196577 A US5196577 A US 5196577A US 40053789 A US40053789 A US 40053789A US 5196577 A US5196577 A US 5196577A
Authority
US
United States
Prior art keywords
compound
affinity
retinoids
crabp
rars
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US07/400,537
Other languages
English (en)
Inventor
Braham Shroot
Yves M. Darmon
Philippe Nedoncelle
Claude Martin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galderma Research and Development SNC
Original Assignee
Centre International de Recherches Dermatologiques Galderma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre International de Recherches Dermatologiques Galderma filed Critical Centre International de Recherches Dermatologiques Galderma
Assigned to CENTRE INTERNATIONAL DE RECHERCHES DERMATOLOGIQUES (C.I.R.D.), SOPHIA ANTIPOLIS reassignment CENTRE INTERNATIONAL DE RECHERCHES DERMATOLOGIQUES (C.I.R.D.), SOPHIA ANTIPOLIS ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: DARMON, YVES M., MARTIN, CLAUDE, NEDONCELLE, PHILIPPE, SHROOT, BRAHAM
Application granted granted Critical
Publication of US5196577A publication Critical patent/US5196577A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/968—High energy substrates, e.g. fluorescent, chemiluminescent, radioactive

Definitions

  • the present invention relates to a new compound, marked with tritium, which is related to retinoids, to its preparation and to its use, in particular, in the determination of the affinity of retinoids for their nuclear receptors and their cytosolic binding protein and/or in the determination of the content of nuclear receptor and cytosolic binding protein cells.
  • retinoids constitute a known class of compounds which act, in particular, on the proliferation and differentiation of numerous types of cells; see, for example, B. A. Pawson et al, Journal of Medicinal Chemistry, Vol. 25, No. 11, pages 1269-1277 (1982).
  • Retinoids have been used, in particular, in the treatment of various dermatological disorders in which an irregularity of the mechanisms for control of the proliferation and differentiation of the epidermal cells is involved; see, for example, the work “Update: Dermatology in General Medicine", edited by Thomas B. Fitzpatrick et al (MacGraw-Hill Book Company), published in 1983, and particularly the chapter by D. B. Windhorst et al, The Retinoids, pages 226-237.
  • retinoids The method of action of retinoids is similar to that of steroids and other effectors interacting with nuclear receptors (Chytil & Ong, 1979).
  • Retinoic acid nuclear receptors (RARs) have been isolated (Daly & Redfern, 1987) and the corresponding complementary DNAs have been cloned and sequenced (Petkovich et al, 1987; Brand et al, 1988).
  • RARa 462 residues
  • RARb (448 residues
  • RAR 458 residues
  • CRABP cellular retinoic acid binding protein
  • the determination of the affinity of a retinoid for the RARs comprises a particularly interesting method of potential biological evaluation of said retinoid.
  • the determination of the affinity for the CRABP provides an additional element of evaluation.
  • a good radioactive ligand must, on the one hand, have a high affinity for its receptors and binding proteins and, on the other hand, have low fixing on any other molecule. In addition, it must be sufficiently stable to be useful in practice.
  • the radioactive ligand generally used is most often tritiated retinoic acid, either in the 2-position (J. Labelled Compounds and Radiopharmaceuticals XVIII, p. 1099 (1980)) or in the 4-position (German Patent Application No. 3,142,975).
  • Retinoic acid certainly has an excellent affinity for RARs and CRABP, with low non-specific fixing, but the molecule has the disadvantage of becoming rapidly degraded, by radiolysis, oxidation and photolysis.
  • tritiated 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid constitutes a new radioactive ligand which has an excellent affinity for RARs and CRABP, with low non-specific fixing.
  • this new ligand is very stable and can be obtained with high specific activity, which makes it particularly useful for the measurement of the affinity of retinoids for RARs and CRABP.
  • the present invention therefore relates to 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid marked with tritium.
  • the present invention relates to a new radioactive ligand, as defined above, having a specific activity of greater than 30 Ci/mmole and preferably at least equal to 50 Ci/mmole, or approximately 1875 GBq/mmole.
  • the present invention also relates to a method for the preparation of the new radioactive ligand, such as defined above.
  • This method is principally characterized by the fact that a multihalogenated alkyl ester of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid is prepared Depending on the number of equivalents of the halogenation agent selected, up to five atoms of halogen can be added. The halogenated alkyl ester is then submitted to the action of a tritiated reducing agent.
  • the reducing agent is, for example, tritium which is used in the presence of 10% palladium on carbon, and triethylamine.
  • the reduction of the halogenated derivative is preferably carried out at room temperature and under ambient pressure, for example, at 15°-30° C. under a pressure of 1 bar (which is approximately 10 5 Pa).
  • the alkyl ester is then saponified in a methanol medium in the presence of soda.
  • the halogenated derivative used as the starting product is preferably the brominated derivative.
  • the alkyl ester used is preferably the ethyl ester.
  • the halogenated alkyl ester of 4-(5,6,7,8-tetrahydro-2-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid can itself be prepared from the alkyl ester of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid by the action of a halogenation agent (in particular a bromination agent).
  • a halogenation agent in particular a bromination agent
  • the brominated derivative can be obtained by the action of bromine in acetic acid at room temperature and under a nitrogen atmosphere.
  • compound I 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid is a known product (hereinafter called "compound I") and can be obtained using the method described, for example, in European Patent Application No. 86.401671 (210.929) filed Jul. 25, 1986.
  • the radioactive ligand of the present invention can also be obtained starting from the alkyl ester of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid by isotopic exchange with tritiated water in the presence of platinum and acetic acid at a temperature preferably ranging from 60° to 150° C.
  • the isotopic exchange is preferably carried out with the aromatic protons of the ligand.
  • the present invention also relates to the use of tritiated 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid as a radioactive marker, in particular in the determination of the affinity, of the presence or of the content of retinoids and/or in the quantification of the RARs and CRABP of said retinoids.
  • the radioactive marker of the invention can be used during the purification of RARs and CRABP using conventional methods of exclusion chromatography under low or high pressure; it is sufficient to add to the cells (in the case of RARs) or to the tissue extract (in the case of CRABP), used as starting products, a determined quantity of the radioactive ligand.
  • the RARs and CRABP are thus marked and their presence o their absence in a given fraction can easily be marked.
  • the knowledge of the fixing curves on the RARs or CRABP also enables the use of the marker of the invention in the quantification of endogenous RARs or those obtained by transfection methods, or in the quantification of CRABP.
  • the present invention also relates to the use of tritiated compound I:
  • retinoic acid as a radioactive marker to locate, titrate or mark the nuclear receptors of retinoic acid:
  • retinoids as a radioactive marker to measure the affinity of retinoids for CRABP.
  • the radioactive marker of the present invention can also be used in the characterization of antibodies against compound I, with these antibodies (obtained using conventional methods for obtaining antihapten antibodies) themselves being usable in the determination of the quantity of product I fixed or unfixed on the RARs and/or the CRABP.
  • the marked antibodies are used to carry out a radioimmunodosage.
  • the radioactive marker of the present invention can also be used in the study of the mechanism for intracellular action and of the general mechanism of compound I in vivo and in the cells and cellular extracts, and also for studying the in vivo as well as cellular and subcellular distribution of said compound and of retinoids in general.
  • FIGS. 1A and 1B represent the high performance exclusion chromatography (HPSEC) profile in the detection of retinoic acid nuclear receptors, respectively;
  • FIGS. 2A and 2B represent the HPSEC profiles in the detection of the fixing of the compound of Example 1 and retinoic acid on RARs, respectively;
  • FIGS. 3a, 3b, 3c and 3d represent the HPSEC profiles of the affinity of compound I, compound IV, retinoic acid and compound VIII for RARs, respectively;
  • FIG. 4 represents the linear regression between the biological retinoids, retinol, retinoic acid, compounds I, II, III, IV, V, VI and VIII and their affinity for RARs;
  • FIGS. 5A and 5B illustrate the fixing of retinoic acid and compounds I, respectively on CRABP.
  • the organic phase was separated, washed with water and then using a saturated solution of sodium bicarbonate and finally sodium thiosulfate.
  • reaction medium was stirred for 2 hours under a tritium atmosphere (1 atmosphere).
  • the catalyst was then filtered, and the labiles were removed twice using 10 ml of a mixture composed of 50% ethanol and 50% acetonitrile.
  • the product was dissolved with 100 ml of ethanol.
  • the final product was dissolved in 100 ml of methanol. Its purity was verified by thin layer chromatography (silica; eluent as above). A single spot was apparent under UV irradiation (254 and 66 nm) and during beta counting.
  • the total activity obtained was 52.8 Ci/mmole.
  • the nucleosol containing RARs was extracted from the purified nuclei using the method described by Daly and Redfern (1987) (that is, after treatment using DNAase and NaCl 0.6M), and analyzed using high performance exclusion chromatography (HPSEC). 50 ⁇ l of marked extract were injected on a 9 ⁇ 250 mm GF250 column (Dupont de Nemours). The elution was carried out in a buffer 0.3M KH 2 PO 4 pH 7.8 at a rate of 1 ml/min. The protein content was followed by measuring the optical density at 280 nm. 28 fractions of 0.3 ml each were collected and counted in Picofluor (Packard) scintillating agent.
  • Picofluor Packard
  • the number of bonded molecules was determined using the surface of the radioactivity peak and the calculated concentration of demi-saturation (C50).
  • 50% inhibitor concentrations (IC50) were calculated, with the compound of example I being used at a concentration of 2.10 -9 M.
  • the molecular weight calibration of the column was carried out using human albumin (67 kDa), ovalbumin (45 kDa) and myoglobin (16.8 kDa).
  • the dose-response curves and the competition curves were analyzed on a computer through non-linear regression using the various forms of the Clark equation.
  • FIG. 1 represents the HPSEC profile in the detection of retinoic acid nuclear receptors (RARs) in a fraction of approximately 45 kDa in the nucleosol of F 9 cells, and enabled the study of the specificity of fixing.
  • RARs retinoic acid nuclear receptors
  • the F 9 cells were incubated with 200 nM of tritiated retinoic acid (A) or the tritiated compound of example 1 (B) in the absence ( ⁇ - ⁇ ) or presence (- ) of 20,000 nM of cold homolog ligand.
  • FIG. 2 gives the results relative to the fixing of retinoic acid and the compound of example 1 on the RARs.
  • the two compounds were used at a concentration of 200 nM.
  • the quantity of ligand bonded to the RARs is expressed in molecules per cell.
  • FIG. 3 shows the comparative experiments carried out with a fixed concentration of 2 nM of the compound of example 1 and variable concentrations of other retinoids (10 -6 M to 10 -10 M).
  • the retinoid examples cited do not have a limiting character.
  • the SPSEC profiles are obtained after incubation of the F9 cells with 2 ⁇ 10 -9 M of the compound of example 1 in the absence (- ) or in the presence of 10 -9 M( ⁇ - ⁇ ), 10 -8 M (- ), 10 -7 M ( ⁇ - ⁇ ), 10 -6 M (- ) of cold competitors.
  • I the unmarked compound of example 1.
  • RA retinoic acid.
  • the inhibition sigmoids given in boxes enabled the determination of the IC50 given in Table 1. For each competition concentration, the peak surface is expressed as a percentage of the surface obtained with the compound of example 1 without competition.
  • the biological activity of the retinoids can be measured on the F9 cells by quantifying the production of the plasminogen activator secreted consecutively with the differentiation of said cells, caused by the retinoids.
  • CPA50 is the concentration of retinoids causing an induction of 50% of the maximum of the secreted plasminogen activator.
  • FIG. 4 represents the linear regression showing an excellent correlation between the biological activity of retinoids (CPA50) and their affinity for the RARs.
  • CPA50 retinoids
  • FIG. 5 The results relating to the fixing of compound I and retinoic acid on CRABP are shown in FIG. 5.
  • the difference (- ) represents the specific bond.
  • the fixing of the claimed compound on CRABP has been characterized by saturation experiments (see FIG. 5b).
  • the total fixing (non-specific+specific (1-1) is obtained by incubation of increasing concentrations (up to a maximum of 125 nM) of the claimed compound with a constant quantity (0.3 ml) of a rat testicle homogenate (CRABP-rich organ).
  • the non-specific fixing of the tritiated compound is determined in parallel, by measuring the fixing with increasing concentrations of the radioactive ligand in the presence of a large excess (1 ⁇ M) of cold homolog ligand ( ⁇ - ⁇ ). An incubation time of two hours is necessary for the establishment of balanced conditions.
  • the tritiated CRABP-ligand complex is separated from the non-bonded ligand by filtration on a Sephadex G25 exclusion gel column (BIO-Rad econo columns, 0.5 ⁇ 20 cm): the complex is eluted (elution peak at 2.5 ml), while the non-bonded ligand is retained in totality on the column. The result is total separation between the bonded and non-bonded product. The elution is done directly in scintillation tubes and the radioactivity is measured by counting.
  • the abscissa on FIG. 1 represent the initial concentrations of the ligand studied, and the ordinates represent the concentrations with the balance of the ligand-binding protein complex.
  • the specific fixing is saturable and reversible.
  • the non-specific fixing is linear and non-saturable in the range of concentrations used, and represents less than 10% of the total fixing.
  • the concentration of CRABP in the rat testicle cytosol used for the experiment can be determined in binding experiments where the marked retinoids are used at a saturating concentration. A value of 10-12 pmol/mg protein is found both with the claimed compound and with the retinoic acid.
  • HPSEC it can be determined that these two ligands are fixed on a molecule with a molecular weight of 15 kDa (molecular weight of the CRABP) with the same elution profile.
  • the Kd value of the retinoic acid is 2 nM, with the non-specific fixing representing approximately 25% of the total fixing.
  • the IC50 concentration of cold ligand reducing the attachment of the tritiated ligand by 50%
  • This IC50 value enables the calculation in each case of the dissociation constant from the balance (Kd) for the cold ligand.
  • Table 1 indicates the values which were determined for the various compounds studies. Identical values were determined if, instead of the claimed compound, marked retinoic acid itself was used in the competition experiments.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
US07/400,537 1988-09-01 1989-08-31 Compound marked with tritium, its preparation and its use in particular in the determination of the affinity of retinoids for their nuclear receptors and their cytosolic binding protein Expired - Lifetime US5196577A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8811469A FR2635683B1 (fr) 1988-09-01 1988-09-01 Nouveau compose marque au tritium, sa preparation et son application notamment dans la determination de l'affinite des retinoides pour leurs recepteurs nucleaires et leur proteine de liaison cytosolique
FR8811469 1988-09-01

Publications (1)

Publication Number Publication Date
US5196577A true US5196577A (en) 1993-03-23

Family

ID=9369652

Family Applications (1)

Application Number Title Priority Date Filing Date
US07/400,537 Expired - Lifetime US5196577A (en) 1988-09-01 1989-08-31 Compound marked with tritium, its preparation and its use in particular in the determination of the affinity of retinoids for their nuclear receptors and their cytosolic binding protein

Country Status (6)

Country Link
US (1) US5196577A (de)
EP (1) EP0359621B1 (de)
JP (1) JP2825867B2 (de)
CA (1) CA1327052C (de)
DE (2) DE359621T1 (de)
FR (1) FR2635683B1 (de)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011217A1 (en) * 1993-10-22 1995-04-27 Ligand Pharmaceuticals Incorporated Isotopically-labeled retinoids, their production and use
US5508456A (en) * 1993-07-30 1996-04-16 Ligand Pharmaceuticals Incorporated 9-cis tritium-labeled retinoids and intermediates, methods for their synthesis and methods for their use in discovering retinoid X receptor ligands
US5514821A (en) * 1994-05-27 1996-05-07 Ligand Pharmaceuticals Incorporated Ring-labeled retinoids and intermediates, and methods for their synthesis and use
US5521391A (en) * 1993-02-18 1996-05-28 Scopus Light (1990) Ltd. Radioactive marker
US5770383A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US5770378A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US5770382A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
RU2163903C2 (ru) * 1998-10-05 2001-03-10 Институт молекулярной генетики РАН Способ введения тритиевой метки в органические соединения и высокомеченный тритием метил-(е)-{2-[6-(2-цианофенокси)пиримидин-4-илокси]фенил}-3-метоксиакрилат
RU2183633C1 (ru) * 2001-05-22 2002-06-20 Институт молекулярной генетики РАН Высокомеченный тритием 2-гидрокси-6-меркаптопурин
RU2197457C1 (ru) * 2001-05-22 2003-01-27 Институт молекулярной генетики РАН Высокомеченный тритием n-метил-n-2-пропинилбензиламин

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2910321B1 (fr) 2006-12-21 2009-07-10 Galderma Res & Dev S N C Snc Gel creme comprenant au moins un retinoide et du peroxyde de benzole
FR2910320B1 (fr) 2006-12-21 2009-02-13 Galderma Res & Dev S N C Snc Emulsion comprenant au moins un retinoide et du peroxyde de benzole
FR2931661B1 (fr) 2008-05-30 2010-07-30 Galderma Res & Dev Nouvelles compositions depigmentantes sous forme d'une composition anhydre sans vaseline et sans elastomere comprenant un derive phenolique solubilise et un retinoide.

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2194535A (en) * 1986-08-29 1988-03-09 Cird Tritium-labelled 2-naphthyl-benzo6thiophene-6-carboxylic acid derivativee

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3142975A1 (de) * 1981-10-29 1983-05-11 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen Verfahren zur herstellung von mit tritium markierterretinsaeure
LU86022A1 (fr) * 1985-07-25 1987-02-04 Cird Derives aromatiques polycyliques,leur procede de preparation et leur application dans les domaines pharmaceutique et cosmetique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2194535A (en) * 1986-08-29 1988-03-09 Cird Tritium-labelled 2-naphthyl-benzo6thiophene-6-carboxylic acid derivativee

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Dawson et al., J. Labelled Cmpds. Radiopharm., vol. 28, No. 1, pp. 89 98. *
Dawson et al., J. Labelled Cmpds. Radiopharm., vol. 28, No. 1, pp. 89-98.
Dawson et al., J. Med. Chem., vol. 32, pp. 1504 1517, (Jul. 1989). *
Dawson et al., J. Med. Chem., vol. 32, pp. 1504-1517, (Jul. 1989).

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521391A (en) * 1993-02-18 1996-05-28 Scopus Light (1990) Ltd. Radioactive marker
US5508456A (en) * 1993-07-30 1996-04-16 Ligand Pharmaceuticals Incorporated 9-cis tritium-labeled retinoids and intermediates, methods for their synthesis and methods for their use in discovering retinoid X receptor ligands
WO1995011217A1 (en) * 1993-10-22 1995-04-27 Ligand Pharmaceuticals Incorporated Isotopically-labeled retinoids, their production and use
US5514821A (en) * 1994-05-27 1996-05-07 Ligand Pharmaceuticals Incorporated Ring-labeled retinoids and intermediates, and methods for their synthesis and use
US5770383A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US5770378A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US5770382A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
RU2163903C2 (ru) * 1998-10-05 2001-03-10 Институт молекулярной генетики РАН Способ введения тритиевой метки в органические соединения и высокомеченный тритием метил-(е)-{2-[6-(2-цианофенокси)пиримидин-4-илокси]фенил}-3-метоксиакрилат
RU2183633C1 (ru) * 2001-05-22 2002-06-20 Институт молекулярной генетики РАН Высокомеченный тритием 2-гидрокси-6-меркаптопурин
RU2197457C1 (ru) * 2001-05-22 2003-01-27 Институт молекулярной генетики РАН Высокомеченный тритием n-метил-n-2-пропинилбензиламин

Also Published As

Publication number Publication date
DE359621T1 (de) 1990-12-20
CA1327052C (fr) 1994-02-15
FR2635683A1 (fr) 1990-03-02
JP2825867B2 (ja) 1998-11-18
EP0359621B1 (de) 1993-07-28
FR2635683B1 (fr) 1990-11-09
EP0359621A1 (de) 1990-03-21
DE68907830D1 (de) 1993-09-02
DE68907830T2 (de) 1994-03-24
JPH02209845A (ja) 1990-08-21

Similar Documents

Publication Publication Date Title
US5196577A (en) Compound marked with tritium, its preparation and its use in particular in the determination of the affinity of retinoids for their nuclear receptors and their cytosolic binding protein
Auberson et al. Improving nonspecific binding and solubility: bicycloalkyl groups and cubanes as para‐phenyl bioisosteres
Schüle et al. Retinoic acid is a negative regulator of AP-1-responsive genes.
Seimbille et al. 18F-labeled difluoroestradiols: preparation and preclinical evaluation as estrogen receptor-binding radiopharmaceuticals
Katzenellenbogen et al. Receptor-binding radiopharmaceuticals for imaging breast tumors: estrogen-receptor interactions and selectivity of tissue uptake of halogenated estrogen analogs
US4880941A (en) Trittum labelled compound, its preparation and its use in the determination of the affinity of retinoids for their cellular receptor
Sanad et al. Radiosynthesis and in silico bioevaluation of 131I‐Sulfasalazine as a highly selective radiotracer for imaging of ulcerative colitis
US5073361A (en) Compound marked with tritium, its preparation and its use in the location of nuclear receptors of retinoids
Parker et al. The nuclear receptor co-repressor RIP140 controls the expression of metabolic gene networks
Lang et al. Synthesis and in vivo biodistribution of F-18 labeled 3-cis-, 3-trans-, 4-cis-, and 4-trans-fluorocyclohexane derivatives of WAY 100635
US5149631A (en) Compound marked with tritium, its preparation and its use in the location of nuclear receptors of retinoids
Dence et al. Carbon-11-labeled estrogens as potential imaging agents for breast tumors
Ishikawa et al. Synthesis and characterization of radioiodinated 3-phenethyl-2-indolinone derivatives for SPECT imaging of survivin in tumors
Ma et al. Liquid chromatography–tandem mass spectrometry identification of metabolites of two 5-HT1A antagonists, N-{2-[4-(2-methoxylphenyl) piperazino] ethyl}-N-(2-pyridyl) trans-and cis-4-fluorocyclohexanecarboxamide, produced by human and rat hepatocytes
Vantrappen et al. A new method for the measurement of bile acid turnover and pool size by a double label, single intubation technique
Mukherjee et al. Development of N-[3-(2′, 4′-dichlorophenoxy)-2-18F-fluoropropyl]-N-methylpropargylamine (18F-fluoroclorgyline) as a potential PET radiotracer for monoamine oxidase-A
Sani et al. Biologically active aromatic retinoids bearing azido photoaffinity-labeling groups and their binding to cellular retinoic acid-binding protein
Irie et al. Photolabile derivatives of indole alkaloid tumor promoter teleocidins: synthesis, biological activities and photoaffinity labeling studies
Zou et al. Discovery of Novel Positron Emission Tomography Tracers for Poly (ADP-Ribose) Polymerase Imaging in Glioblastoma through Photocatalyzed 18F-Fluorination
Lee et al. Synthesis of 7′-[123I] iodo-D-luciferin for in vivo studies of firefly luciferase gene expression
Hall et al. Differential stereoselectivity in the metabolism of benzo [a] pyrene and anthracene by rabbit epidermal and hepatic microsomes
Sirocchi et al. Radiofluorinated Analogs of NCS-382 as Potential PET Tracers for Imaging the CaMKIIα Hub Domain
CA2281523A1 (en) Identification of a unique receptor specific for a particular retinoid inducing cellular apoptosis
Shroot et al. Retinoic Acid Receptor Subtypes
AU4582202A (en) Identification of a unique receptor specific for a particular retinoid inducing cellular apoptosis

Legal Events

Date Code Title Description
AS Assignment

Owner name: CENTRE INTERNATIONAL DE RECHERCHES DERMATOLOGIQUES

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:SHROOT, BRAHAM;DARMON, YVES M.;NEDONCELLE, PHILIPPE;AND OTHERS;REEL/FRAME:005157/0053

Effective date: 19890831

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12